| LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse. | |
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MedLine Citation:
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PMID: 21938018 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We hypothesized that lectin-like oxidized LDL receptor-1 (LOX-1) deletion may inhibit oxidative stress signals, reduce collagen accumulation and attenuate cardiac remodeling after chronic ischemia. Activation of LOX-1 plays a significant role in the development of inflammation, apoptosis and collagen signals during acute ischemia. Wild-type and LOX-1 knockout (KO) mice were subjected to occlusion of left coronary artery for 3 weeks. Markers of cardiac hypertrophy, fibrosis-related signals (collagen IV, collagen-1 and fibronectin) and oxidant load (nicotinamide adenine dinucleotide phosphate oxidase expression, activity of mitogen-activated protein kinases and left ventricular (LV) tissue thiobarbituric acid reactive substances) were analyzed. In in vitro experiments, HL-1 cardiomyocytes were transfected with angiotensin II (Ang II) type 1 receptor (AT1R) or type 2 receptor (AT2R) genes to determine their role in the cardiomyocyte hypertrophy. LOX-1 KO mice had 25% improvement in survival over the 3-week period of chronic ischemia. LOX-1 deletion reduced collagen deposition and cardiomyocyte hypertrophy (∼75%) in association with a decrease in oxidant load and AT1R upregulation (all P<0.05). The LOX-1 KO mice hearts exhibited a disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) expression and matrix metalloproteinase 2 activity, and increased AT2R expression (P<0.05). Attenuation of cardiac remodeling was associated with improved cardiac hemodynamics (LV ±dp/dt and cardiac ejection fraction). In vitro studies showed that it is AT1R, and not AT2R overexpression that induces cardiomyocyte hypertrophy. We demonstrate for the first time that LOX-1 deletion reduces oxidative stress and related intracellular signaling, which leads to attenuation of the positive feedback loop involving AT1R and LOX-1. This results in reduced chronic cardiac remodeling.Gene Therapy advance online publication, 22 September 2011; doi:10.1038/gt.2011.133. |
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Authors:
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J Lu; X Wang; W Wang; H Muniyappa; C Hu; S Mitra; B Long; K Das; J L Mehta |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-22 |
Journal Detail:
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Title: Gene therapy Volume: - ISSN: 1476-5462 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421525 Medline TA: Gene Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1] Central Arkansas Veterans Healthcare System and Departments of Internal Medicine, Pathology and Pharmacology, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA [2] Department of Emergency Medicine, Renmin Hospital of Wuhan University, Wuhan, China. |
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